The objective of this Research Project 3 is to evaluate the effect of electrical acupuncture (EA), specifically the non-invasive HANS method of transcutaneous electric stimulation, for the prevention of drug relapse, and to provide insight into the mechanism of action. Acupuncture is a 3000-year-old Chinese therapy commonly used to treat disease and relieve pain. Recently, the scientific basis of acupuncture has been founded, at least partly, on the frequency-dependent release of opioid peptides in the CNS. For example, high frequency (100-Hz) stimulation is more effective than low frequency (2-Hz) stimulation in reducing the opiate withdrawal syndrome by activating the dynorphin system mediated by kappa opoid receptors, but low frequency is more effective than high frequency in reducing opiate craving by activating the endorphin/enkephalin system mediated by mu/delta opioid receptors. In contrast to opiate addiction, relief from cocaine addiction seems to work through a slightly different mechanism, such that the conditioned place preference (CPP) for cocaine, a rodent model of cocaine craving, can be suppressed by 100-Hz but not by 2-Hz stimulation. Based on the successful experience of the PI's (Dr. Han) previous treatment of patients for heroin withdrawal, we propose to evaluate the potential of the HANS method for the prevention of cocaine relapse, and to investigate the molecular mechanism of action. The specific aims are (1) to further explore the mechanisms of EA suppression of cocaine CPP in rats, including brain areas and chemical mediators involved, using microinjection and brain push-pull perfusion techniques, and immunohistochemical examination, with a focus on brain areas such as the ventral tegmentum, nucleus accumbens, and amygdala, and on neurotransmitters and neuromodulators such as dopamine, enkepahlin, and dynorphin; (2) to use functional magnetic resonance imaging (fMRI) in rats and humans to characterize the difference in brain between cocaine dependent and non-dependent subjects, and the difference between 2-Hz (non effective) and 100-Hz (effective) treatment groups, to verify the findings obtained in Aim 1; and (3) to conduct a randomized, controlled clinical trial to test the effectiveness of HANS in treating cocaine addiction. In the HANS group, real current is delivered to the patient, with skin electrodes applied on the body acupoint Heku (LI 4)/Laogong (P 8) on one hand and Neiguan (P 6)/Waiguan (TE 5) on the other arm. The current can be set to two times threshold (one T = 5 mA). The control group receives a modified (mock) HANS at 2Hz, which is equivalent to "minimal acupuncture". We speculate that the HANS will produce a significantly better therapeutic effect than the mock HANS in suppressing craving and preventing relapse. In summary, acupuncture by transcutaneous electrical stimulation is a highly attractive alternative therapy for the treatment of drug abuse. This approach differs from pharmacological treatment primarily in being a non-invasive, safe way to make the body release its own natural chemicals to prevent relapse.